Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families.

Julia Doll,Naseer Ahmad,Tabea Röder,Indrajit Nanda,Imran Khan,Marcus Dittrich,Barbara Vona,Tyler D Graves,Ajmal Khan,Noor Muhammad,Laura Kühlewein,Franz Rüschendorf,Tobias Müller,Susanne M Kolb,Thomas Haaf,Sher Alam Khan,Linda Schnapp,Lawrence C Layman,Saadullah Khan,Hamed Nawaz,Il-Keun Kong ,Jonathan D J Labonne ,Michaela A.h Hofrichter ,Hyung Goo Kim

doi:10.3390/genes11111329

Abstract

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

Highlights

In parts of the world where consanguinity is prevalent, it is not uncommon to see a high prevalence of genetic diseases
Using Exome sequencing (ES) and bioinformatics analysis, 13 different variants in seven hearing loss (HL)-associated genes were identified, including two that have not been previously described in the literature (15.4%)
Pathogenic and likely pathogenic variants were identified in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A (Table 1)

Summary

Introduction

In parts of the world where consanguinity is prevalent, it is not uncommon to see a high prevalence of genetic diseases. The consanguineous marriage rates in Pakistan are among the highest worldwide [1]. 60% of marriages in Pakistan are consanguineous, with roughly 80%. The prevalence of autosomal recessive diseases associated with a monogenic background, such as profound hearing loss (HL), is high in countries where consanguineous marriages are common [3]. Hereditary HL is one of the most prevalent sensory disorders that affects 1 to 2 per 1000 live births worldwide. Over 120 genes have been identified as causing non-syndromic hearing loss (NSHL), which comprises approximately 70% of all forms of hereditary HL (http://hereditaryhearingloss.org)

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Discussion

Conclusion